P377: A PHASE II TRIAL OF MINI-HYPER-CVD WITH VENETOCLAX FOR PATIENTS WITH RELAPSED/REFRACTORY (R/R) PHILADELPHIA CHROMOSOME (PH)-NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
Authors: Fadi Haddad, Elias Jabbour, Marianne Zoghbi, Nicholas Short, Jayastu Senapati, Walid Macaron, Cedric Nasnas, Lewis Nasr, Naveen Pemmaraju, Nitin Jain, William G. Wierda, Gautam Borthakur, Guillermo Montalban-Bravo, Farhad Ravandi, Guillermo Garcia-Manero, Tapan Kadia, Kelly Chien, Jennifer Thankachan, Rebecca Garris, Hagop Kantarjian
Journal: HemaSphere (2023)

Background: In preclinical studies, Venetoclax (Ven), an orally active Bcl-2 antagonist, has shown promising clinical activity in patients (pts) with R/R ALL. The combination of Ven with low intensity mini-Hyper-CVD chemotherapy could improve outcomes in this setting. Aims: The aim of our study is to evaluate the efficacy and tolerability of Ven added to mini-Hyper-CVD chemotherapy in pts with R/R ALL. Methods: Pts ≥18 years with R/R Ph-negative B- or T-cell ALL were eligible. Pts were required to have a PS of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3 x ULN and creatinine ≤2 mg/dl. Pts received mini-Hyper-CVD alternating with methotrexate and cytarabine for up to 8 cycles (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). Ven was given at a dose of 400 mg/d on Days (D) 1-14 of Cycle (C) 1 and on D1-7 of C2-8. Rituximab (if CD20+ B-ALL) and prophylactic IT chemotherapy x8 doses were given for the first 4 cycles. Pts with T-ALL received additional 2 cycles of nelarabine and peg-asparaginase during consolidation without Ven, and 2 cycles of nelarabine plus peg asparaginase during maintenance. Responding pts received vincristine and prednisone maintenance with venetoclax daily on days 1-14 of each 28-day cycle for up to 2 years. Results: Between 6/2019 and 2/2021, 23 pts were treated, with a median age of 45 years (range, 20-70). 18 (78%) pts had B-ALL and 5 (22%) T-ALL, including 1 pt with ETP ALL. Among the 23 pts, the median number of prior therapies was 2 (range, 1-6) and 13 (57%) had undergone prior allogeneic stem cell transplant (ASCT). Among the 18 B-ALL pts, 16 (89%) had received prior blinatumomab and 7 (39%) prior inotuzumab. Among 23 pts, 1 was in CR at enrollment. Overall, 12 of 22 (55%) pts responded to therapy (complete response, n=9), of whom 9 achieved best response after C1 and 3 after C2. An additional pt achieved partial response. The overall response rate among the 18 pts who had at least a bone marrow assessment after C1 was 67%. The median duration of follow-up was 26 months (range, 2-35). Among the 13 responders (including the pt in CR at start), 6 (46%) relapsed, 5 (39%) underwent ASCT (4 subsequently relapsed), and 2 (15%) died in remission. The median RFS and OS were 6.4 and 8.1 months, respectively, and the 1-year RFS and OS rates were 15% and 37%, respectively. Survival was worse in pts with adverse cytogenetics versus others (median OS, 6 vs 12 months; 1-yr OS rate, 17% vs 44%; P=0.15). In C1, the median time to platelet recovery was 27 days (range, 0-81) and neutrophil recovery was 21 days (range, 0-36); in C2+, median times to recovery were 25 days (range, 0-76) and 15 days (range, 0-26), respectively. The 30-day and 60-day mortality rates were 0% and 13%, respectively. Summary/Conclusion: In pts with R/R Ph-negative ALL, the combination of low-intensity chemotherapy mini-Hyper-CVD with Ven demonstrated clinical efficacy with a response rate of 67% and a favorable safety profile. Further studies examining the role of Ven-based therapies in ALL are needed for newly diagnosed and R/R pts.Keywords: Acute lymphoblastic leukemia, Venetoclax, Phase II